Chronic stress is a factor in psychiatric diseases, such as depression, PTSD and other anxiety disorders. The brain noradrenergic system plays an important role in arousal and acute stress reactivity, and has been implicated in the etiology and symptoms of such stress-related psychiatric disorders. In the previous project, we showed that norepinephrine (NE) acts in limbic and hypothalamic brain regions to facilitate adaptive behavioral and neuroendocrine responses to acute stress. We found that differences in this modulatory influence may account for genetic vulnerability to stress in WKY rats, and that interactions between genetic predisposition and environmental stress can lead to maladaptive changes in behavioral and endocrine stress reactivity that resemble stress-related pathology. In this renewal, we continue this investigation, shifting focus from the beneficial modulatory effect of NE in acute stress to examine its role in the detrimental effects of chronic stress, specifically on emotion and cognition. Aims 1 and 2 address possible changes in acute NE modulatory function as a consequence of chronic unpredictable stress (CUS). Aim 1 will test the hypothesis that CUS-induced sensitization of acute NE reactivity in the bed nucleus of the stria terminals underlies the CUS-induced increase in anxiety-like behavior. Aim 2 will address cognitive function in medial prefrontal cortex (mPFC). We have shown that enhancing NE function in mPFC facilitates cognitive set-shifting, an executive process that is disrupted in depression and anxiety disorders. By contrast, CUS causes a set-shifting deficit. In aim 2, we determine whether the facilitatory influence of NE on cognitive function in mPFC is intact after CUS, when the cognitive deficit is evident. If intact, we will investigate if increased NE is recruited to compensate for the cognitive deficit after CUS. But if deficient, we will determine if the deficit is pre-synaptic (NE release) or post-synaptic (adrenergic receptor expression or function in mPFC). These studies will employ microdialysis, behavioral pharmacology, and anatomical approaches. In aim 3, we will explore the potential role of repeated activation of noradrenergic facilitatory activity during chronic stress as a causative factor in the CUS-induced cognitive deficit, rather than simply an effect. We hypothesize that repeatedly evoked NE activity during CUS may be responsible for changes in mPFC function that underlie the deficit in cognition. This will be tested by blocking noradrenergic influence in mPFC during CUS, but leaving the facilitatory function intact at testing. A complementary battery of approaches will be used, including systemic adrenergic antagonist treatment during CUS, lesioning noradrenergic innervation of mPFC, and blocking adrenergic receptors locally in mPFC before each CUS stress treatment. Understanding how maladaptive changes in NE function induced by chronic stress may account for cognitive and affective dimensions of depression and anxiety disorders may lead to more effective strategies for the treatment or prevention of these devastating neuropsychiatric disorders. Chronic stress is an important factor in the development of many serious psychiatric disorders, and the brain noradrenergic system, which is involved in the response to stress, is a target for many therapeutic agents used in the treatment of stress-related illnesses such as depression, PTSD and anxiety disorders. In this project, we investigate how the modulatory function of norepinephrine, which is normally beneficial in the short-term, can become detrimental if activated repeatedly in the context of chronic stress. This is important to understanding the processes leading to stress-related psychopathology, and the results will hopefully inform the future development of novel strategies for more effective treatment or even prevention of these devastating and costly stress-related neuropsychiatric disorders.